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Chemical Modification of Linkers Provides Stable Linker-Payloads for the Generation of Antibody-Drug Conjugates.

ABSTRACT: Stability of antibody-drug conjugates (ADCs) in mouse serum is one of the critical requirements for the evaluation of ADCs in mouse tumor models. Described herein is a strategy to address the mouse serum instability of uncialamycin linker-payloads through various chemical approaches that involve modification of different parts of the linker and payload. This effort ultimately led to the identification of a m-amide p-aminobenzyl carbamate (MA-PABC) group that resulted in linkers with dramatic improvement of mouse serum stability without affecting the desired proteolytic cleavage.

SUBMITTER: Poudel YB

PROVIDER: S-EPMC7667830 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Chemical Modification of Linkers Provides Stable Linker-Payloads for the Generation of Antibody-Drug Conjugates.

Poudel Yam B YB Chowdari Naidu S NS Cheng Heng H Iwuagwu Christiana I CI King H Dalton HD Kotapati Srikanth S Passmore David D Rampulla Richard R Mathur Arvind A Vite Gregory G Gangwar Sanjeev S

ACS medicinal chemistry letters 20200922 11

Stability of antibody-drug conjugates (ADCs) in mouse serum is one of the critical requirements for the evaluation of ADCs in mouse tumor models. Described herein is a strategy to address the mouse serum instability of uncialamycin linker-payloads through various chemical approaches that involve modification of different parts of the linker and payload. This effort ultimately led to the identification of a <i>m</i>-amide <i>p</i>-aminobenzyl carbamate (MA-PABC) group that resulted in linkers wit ...[more]

PMID: 33214828

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